Cobalt-mediated contractile dysfunction in adult hearts and consequent effects on cardiomyocyte calcium transients

Introduction Exposure to circulating cobalt levels in patients with metal-on-metal hip replacements has been implicated in the development of cardiac hypertrophy and heart failure, yet the specific underlying causative mechanism(s) are unknown.
Methods We have used a rat model to examine both chronic and acute effects of cobalt chloride (CoCl2) on cardiac parameters at both whole organ and cellular levels. For chronic effects, experimental adult male rats (180-220g) received daily intraperitoneal (IP) injections of either vehicle (n≤10) or 1mg/kg CoCl2 (n≤14) for 28 days. Heart function was assessed post-treatment using echocardiography and the cobalt content in whole blood, heart tissue and cardiac myocytes (CM) measured by ICP-MS. Rats were anaesthetised via IP injection with 0.1μg/kg Dolethal containing 0.1μl heparin sodium and upon loss of reflex, hearts removed for processing. CM were isolated from both experimental and naïve rat hearts to assess both the chronic (28 day) and acute effects of cobalt on intracellular calcium handling studied using live single cell confocal microscopy. Naïve CM were treated with 1, 10 and 100μM CoCl2 for 5min, 1h and 24h.
Results Rats treated with CoCl2 for 28 days showed normal weight gain over the experimental period (vehicle: 59.6±4%, n=10; CoCl2: 55.9±2.3%, n=14) with no changes in heart weight (vehicle: 1.3±0.2g, n=5; CoCl2: 1.3±0.1g, n=6) but evidence of impaired contractility (% fractional shortening; vehicle: 61.5±3.5%, n=10; CoCl2: 53.6±1.4%, n=14; p1h consistently resulted in deterioration of CM viability. Conclusion Taken together, these results suggest that CoCl2 has a negative chronic inotropic effect on the heart. These effects are associated with reduced Ca2+ release in isolated myocytes exposed to CoCl2 acutely and chronically. Future work will focus on the cellular mechanisms involved.